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Dopamine D2 receptor knockout mice develop features of Parkinson disease

Authors

  • Rogan B. Tinsley PhD,

    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
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  • Chris R. Bye BSc (Hon),

    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
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  • Clare L. Parish PhD,

    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
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  • Angela Tziotis-Vais BSc (Hon),

    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
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  • Sonia George PhD,

    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
    2. Department of Pathology, the University of Melbourne, Parkville, Australia
    3. Centre for Neuroscience, the University of Melbourne, Parkville, Australia
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  • Janetta G. Culvenor PhD,

    1. Department of Pathology, the University of Melbourne, Parkville, Australia
    2. Centre for Neuroscience, the University of Melbourne, Parkville, Australia
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  • Qiao-Xin Li PhD,

    1. Department of Pathology, the University of Melbourne, Parkville, Australia
    2. Centre for Neuroscience, the University of Melbourne, Parkville, Australia
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  • Colin L. Masters MD,

    1. Mental Health Research Institute, Parkville, Australia
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  • David I. Finkelstein PhD,

    1. Centre for Neuroscience, the University of Melbourne, Parkville, Australia
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  • Malcolm K. Horne MD, PhD

    Corresponding author
    1. Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia
    2. Centre for Neuroscience, the University of Melbourne, Parkville, Australia
    3. Department of Neurology, St Vincent's Hospital, Fitzroy, Australia
    • Howard Florey Institute, University of Melbourne, VIC 3010, Parkville, Australia
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  • Potential conflict of interest: Nothing to report.

Abstract

Objective

This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α-synuclein–containing cytoplasmic inclusion of Parkinson disease (PD).

Methods

Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy.

Results

LB-like cytoplasmic inclusions containing α-synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild-type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α-synuclein immunoreactivity in SNpc neurons increased with age in both wild-type and D2R(−/−) mice, most likely because of redistribution of α-synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc.

Interpretation

Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB-like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484

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